Vietata la copia non autorizzata: tutti i diritti del produttore e il

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Vietata la copia non autorizzata: tutti i diritti del produttore e il materiale sono riservati. Solo per uso privato. Il materiale contenuto in questo file è ad uso esclusivo dei partecipanti al corso ECM residenziale tenutosi il 12 ottobre 2011. Ogni altro uso (uso in pubblico e diffusione) è strettamente proibito senza il permesso esplicito del produttore La Gestione del Tromboembolismo Venoso:
Confronto tra Farmaci “Classici”
e Nuove Prospettive Terapeutiche
Franco Piovella
S.C. ANGIOLOGIA - MALATTIE TROMBOEMBOLICHE
Fondazione IRCCS Policlinico San Matteo
Pavia
Tromboembolismo Venoso
Malattie Tromboemboliche - Pavia
Il Trattamento del TEV, 2010
UFH (e.v., s.c., s.c. a dosi fisse)
EBPM
Fondaparinux
Trombolisi
Antagonisti della vitamina K
INR 2.0-3.0
Trattamento a lungo termine
INR 2.0-3.0 oppure:
INR 1.5-1.9
Trattamento esteso
≥ 5 giorni
almeno tre mesi
indefinito*
* Con rivalutazione del rapporto rischio/beneficio individuale ad intervalli periodici
Obiettivi del Trattamento
Scopo del trattamento anticoagulante iniziale
Eliminare la generazione di trombina
Prevenire la estensione del trombo
Prevenire l’embolia polmonare e le recidive fatali
Trattamento esteso
≥ 5 giorni
almeno tre mesi
indefinito*
Scopo del trattamento anticoagulante a lungo termine
Stabilizzare il trombo
Prevenire le recidive precoci
Trattamento esteso
≥ 5 giorni
almeno tre mesi
indefinito*
Scopo del trattamento anticoagulante esteso
Prevenire le recidive tardive
ed i nuovi episodi non correlati
all’evento iniziale
Trattamento esteso
≥ 5 giorni
almeno tre mesi
indefinito*
Bersagli dei Farmaci Anticoagulanti
Via Intrinseca
(attivazione da contatto)
XII
Via Estrinseca
(danno tissutale)
XIIa
XI
Tissue factor
XIa
IX
IXa
VIII
VII
VIIa
VIIIa
Xa
X
V
Va
II
Fibrinogeno
IIa
(Trombina)
Fibrina
Via Intrinseca
XII
Via Estrinseca
(danno tissutale)
XIIa
XI
Tissue factor
XIa
IX
IXa
VIII
Eparina
VII
VIIa
VIIIa
Xa
X
V
Va
II
Fibrinogeno
IIa
(Trombina)
Fibrina
Via Intrinseca
XII
Via Estrinseca
(danno tissutale)
XIIa
XI
Tissue factor
XIa
IX
IXa
VIII
Eparina
Antagonisti della
Vitamina K
VII
VIIa
VIIIa
Xa
X
V
Va
II
Fibrinogeno
IIa
(Trombina)
Fibrina
Via Intrinseca
XII
Via Estrinseca
(danno tissutale)
XIIa
XI
Tissue factor
XIa
IX
IXa
VIII
Eparine e LMWH
Antagonisti della
Vitamina K
VII
VIIa
VIIIa
Xa
X
V
Va
II
Fibrinogeno
IIa
(Trombina)
Fibrina
Via Intrinseca
XII
Via Estrinseca
(danno tissutale)
XIIa
XI
Tissue factor
XIa
IX
IXa
VIII
Eparine e LMWH
Antagonisti della
Vitamina K
Inibitori diretti della
trombina
VII
VIIa
VIIIa
Xa
X
V
Va
II
Fibrinogeno
IIa
(Trombina)
Fibrina
Via Intrinseca
XII
Via Estrinseca
(danno tissutale)
XIIa
XI
Tissue factor
XIa
IX
IXa
VIII
Eparine e LMWH
Antagonisti della
Vitamina K
Inibitori diretti della
Trombina
Inibitori del Fattore Xa
VII
VIIa
VIIIa
Xa
Xa
X
V
Va
II
Fibrinogeno
IIa
(Trombina)
Fibrina
Prevention of DVT in Orthopaedic Surgery
ive Hip Replacement - Data Obtained with Venogr
Prophylaxis
n° of Studies
% Tot. DVT
(95%C.I.)
RRR, %
% Prox. DVT
(95%C.I.)
RRR, %
Controls (n.t.)
12
54.2
(50-58)
-
26.6
(23-31)
-
El. Stockings
Aspirin
LD Heparin
Warfarin
IPC
Rec. Hirudin
4
6
11
13
7
3
41.7
40.2
30.1
22.1
20.3
16.3
(36-48)
23
26
45
59
63
70
25.5
11.4
19.3
5.2
13.7
4.1
(21-31)
4
57
27
80
48
85
3
4
15.6
14.0
(12-19)
71
74
4.1
10.2
(2-6)
Danaparoid
AD Heparin
(35-45)
(27-33)
(20-24)
(17-24)
(14-19)
(10-19)
(8-16)
(17-22)
(4-6)
(11-17)
(3-5)
(7-14)
ACCP Consensus 2008
85
62
Prevention of DVT in Orthopaedic Surgery
ive Hip Replacement - Data Obtained with Venogr
Prophylaxis
n° of Studies
% Tot. DVT
(95%C.I.)
Controls (n.t.)
12
54.2
(50-58)
El. Stockings
Aspirin
LD Heparin
Warfarin
IPC
Rec. Hirudin
LMWH
Danaparoid
AD Heparin
4
6
11
13
7
3
30
3
4
41.7
40.2
30.1
22.1
20.3
16.3
16.1
15.6
14.0
(36-48)
(35-45)
(27-33)
(20-24)
(17-24)
(14-19)
(15-17)
(12-19)
(10-19)
RRR, %
% Prox. DVT
(95%C.I.)
RRR, %
-
26.6
(23-31)
-
23
26
45
59
63
70
70
71
74
25.5
11.4
19.3
5.2
13.7
4.1
5.9
4.1
10.2
(21-31)
4
57
27
80
48
85
78
85
62
(8-16)
(17-22)
(4-6)
(11-17)
(3-5)
(5-7)
(2-6)
(7-14)
ACCP Consensus 2008
L’EPARINA A BASSO PESO MOLECOLARE NEL
TRATTAMENTO DELLA TROMBOSI VENOSA PROFONDA
UFH (n)
LMWH (n)
p
Prandoni et al.
1992
14% (85)
7% (85)
p=0.13
Emorr. Maggiori
3.5%
0.1%
p>0.2
Hull et al.
1992
6.9% (219)
2.8% (213) p<0.05
Emorr. Maggiori
5%
0.5%
95% C.I.
-0.3-15%
0.02-8.1%
p=0.006
Koopman MMW, Prandoni P, Piovella F, et al.
Treatment of venous thrombosis with intravenous
unfractionated heparin administered in the hospital as
compared with subcutaneous low-molecular-weight
heparin administered at home
Tasman Study
N Engl J Med 1996;334:682-7
Levine M, Gent M, Hirsh J, et al.
A comparison of low-molecular-weight heparin
administered primarily at home with unfractionated
heparin administered in the hospital for proximal
deep-vein thrombosis
Canadian Study
N Engl J Med 1996;334:677-81
Home treatment of DVT with
LMWHs is as effective and safe
as in-hospital UFH
The TASMAN study
8.6%
8.1%
6.9%
6.9%
Nadroparin
UFH
2.0%
0.5%
% VTE recurrence
Major bleeding
Overall mortality
Koopman MWM, Prandoni P, Piovella F., et al. N Engl J Med 1996;334:682–
1996;334:682–7.
The Columbus Investigators
Low-molecular-weight heparin in the treatment of
patients with venous thromboembolism
Columbus Study
N Engl J Med 1997;337:657-62
Simonneau G, Sors H, Charbonnier B, et al.
A comparison of low-molecular-weight heparin with
unfractionated heparin for acute pulmonary
embolism
Thésée Study
N Engl J Med 1997;337:663-9
COLUMBUS and THÉSÉE studies.
Main results
COLUMBUS
LMWH
(n=510)
THÉSÉE
UFH
(n=511)
LMWH
(n=304)
UFH
(n=308)
Recurrent VTE
27 (5.3%)
25 (4.9%)
5 (1.6%)
6 (1.9%)
Major bleeding
16 (3.1%)
12 (2.3%)
6 (2.0%)
8 (2.6%)
Mortality
36 (7.1%)
39 (7.6%) 12 (3.9%) 14 (4.5%)
Columbus Study
N Engl J Med 1997;337:657-62
Thésée Study
N Engl J Med 1997;337:663-9
Recurrent symptomatic VTE, major bleeding and mortality at three
months – summary of two meta-analyses in deep vein thrombosis
and pulmonary embolism –
Low Molecular
Weight Heparin
Unfractionated
Heparin
Odds Ratio
(95% CI)
86/1998 (4.3%)
113/2021 (5.6%)
Major bleeding
30/2353 (1.3%)
51/2401 (2.1%)
Mortality
135/2108 (6.4%)
172/2137 (8.0%)
0.75
(0.55-1.01)
0.60
(0.39-0.93)
0.78
(0.62-0.99)
30/988 (3.0%)
39/895 (4.4%)
Major bleeding
14/1023 (1.4%)
21/928 (2.3%)
Mortality
46/988 (4.7%)
55/895 (6.1%)
Deep Vein Trombosis
Recurrent VTE
Pulmonary Embolism
Recurrent VTE
A. van den Belt et al. 2002, The Cochrane Library
D. Quinlan et al. 2004, Ann Intern Med
0.68
(0.42-1.09)
0.67
(0.36-1.27)
0.77
(0.52-1.15)
Anticoagulants in Development
TTP889
TF/VIIa
TFPI (tifacogin)
NAPc2
IX
X
VIIIa
IXa
Oral
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
YM150
Va
Xa
Oral
Dabigatran
II
IIa
Fibrinogen
APC (drotrecogin alfa)
sTM (ART-123)
Fibrin
Parenteral
Fondaparinux
Idraparinux
Biotinylated idraparinux
Adapted from Bates Br J Haematol 2006
Fondaparinux
Description
* fully synthetic
* potent and indirect selective Xa inhibitor
Clinical evaluation
* prevention VTE after orthopaedic surgery
* treatment of established VTE
* treatment of acute coronary syndromes
Fondaparinux
Heparins
Long chains capture other
factors as thrombin
Pentasaccharide
sequence
Arg
Lys
thrombin
Arg
trombina
factor Xa
Xa
factor
AT
Chirurgia Ortopedica Maggiore
Il Fondaparinux nella
prevenzione del TEV in
chirurgia ortopedica
Studi di fase III - efficacia
Anca
Ginocchio
Anca
Frattura
Fondaparinux meglio
Anca
Anca
Frattura
EPHESUS
N = 1817
PENTATHLON 2000 (N.A.)
PENTAMAKS (N.A.)
EPHESUS (EU)
PENTHIFRA (EU)
Exact 95% CI
Enoxaparina meglio
[72.9; 37.5]
58.5%
PENTATHLON 2000
N = 1584
[52.2; 7.6]
28.1%
PENTHIFRA
N = 1250
[73.4; 45.0]
61.6%
Ginocchio PENTAMAKS
N = 724
[75.5; 44.8]
63.1%
P = 10 -17
Overall odds
reduction
[63.2; 45.8]
55.3%
% odds reduction
-100
-80
-60
-40
-20
0
20
40
60
80
100
Linee guida ACCP
Seventh ACCP Conference on Antithrombotic
and Thrombolytic Therapy
•
Ai pazienti sottoposti ad artroprotesi elettiva d’anca o di ginocchio
dovrebbe essere prescritta una delle seguenti profilassi:
— LMWH
— Fondaparinux
— AVK con target INR = 2.5
•
(grado 1A)
(grado 1A)
(grado 1A)
Patients undergoing hip fracture surgery should receive either:
—
—
—
—
Fondaparinux
LMWH
AVK con target INR = 2.5
Eparina NF a basse dosi
(grado
(grado
(grado
(grado
1A)
1C+)
2B)
1B)
• Profilassi antitrombotica per almeno 10 giorni (grado 1A), estesa a
28-35 giorni per protesi d’anca e chirurgia per frattura d’anca
Chest 2004; 126 (3 Suppl): 163S-696S
Gli Studi Matisse
Outcome Primario di Efficacia
MATISSE PE1
Fondaparinux (n=1,103)
UFH (n=1,110)
EP fatale
16 (1.5%)
15 (1.4%)
EP non fatale o TVP
26 (2.4%)
41 (3.6%)
Recidive di TEV totali sintomatiche
42 (3.8%)
56 (5.0%)
-3.0%
-1.2%
Δ=3.5%
0 0.5%
Fondaparinux - UFH (95% CI)
MATISSE DVT2
Fondaparinux (n=1,098)
EP fatale
LMWH (n=1,107)
5 (0.5%)
5 (0.5%)
EP non fatale o TVP
38 (3.5%)
40 (3.6%)
Recidive di TEV totali sintomatiche
43 (3.9%)
45 (4.1%)
-1.8%
-0.15%
0
1.5%
Δ=3.5%
Fondaparinux - LMWH (95% CI)
1. The Matisse Investigators. N Engl J Med, 2003.
2. The Matisse Investigators. Ann Intern Med, 2004
Outcome Primario di Sicurezza:
Trattamento Iniziale
MATISSE PE1
Fondaparinux
1.3%
UFH
1.1%
0%
4.5 %
3.2%
6.3 %
5.2%
2%
4%
Emorr.
maggiore
6%
8%
Emorr. non-maggiore,
clinicamente rilevante
MATISSE DVT2
Fondaparinux
1.1%
LMWH
1.2%
0%
3.7%
2.6%
4.2%
3.0%
2%
1. The Matisse Investigators. N Engl J Med, 2003
2. The Matisse Investigators. Ann Intern Med, 2004
4%
6%
8%
Treatment of VTE
Initial treatment
5 to 7 days
LMWH or Fondaparinux or UFH
> 3 months
Long-term therapy
Vitamin K antagonist (INR 2.0 - 3.0)
Decousus H, Prandoni P, Mismetti P, et al.
Fondaparinux for the treatment of
Superficial Vein Thrombosis
N Engl J Med 2010; 363: 1222-32
Study Design
Primary Efficacy Outcome:
Symptomatic Thromboembolic
Complications/Death
Fondaparinux
2.5 mg od
n=1501
Randomization
Elastic stockings,
topical NSAIDs and
pain killers allowed
Double-blind treatment
during 45 days
Follow-up
Placebo
n=1501
Day 45±2
Day 75±2
Symptomatic Thromboembolic
Complications/ Death (%)
Primary Efficacy Outcome (Day 47)
RRR 85.2%
7
(95% CI= 73.7 to 91.7)
6
p<0.001
5.9%
n=88
5
4
3
2
1
0.9%
n=13
0
Fondaparinux 2.5 mg
Placebo
Primary efficacy outcome: Symptomatic PE, DVT, Extension
of the initial SVT, Recurrent SVT, All-cause death
Conclusion
• Once-daily fondaparinux 2.5 mg for 45 days is
effective, well tolerated and widely applicable for the
treatment of patients with symptomatic lower-limb
SVT without concomitant DVT/PE at inclusion
• The benefit of fondaparinux persists beyond the end
of treatment
POTENTIAL VTE MANAGEMENT LANDSCAPE
Agent
Half life
(hrs)
Bioavailability
Elimination
Dosing/Class
Prodrug
Antidote
IDRA(biota)PARINUX
80-130
100%
renal
once weekly
s.c. indirect aXa
No
Yes
14-17
5%
80% renal
q.d. oral
direct T.I.
Yes
No
RIVAROXABAN
5-13
>80%
1/3 renal
2/3 hepatic
b.i.d./q.d. oral
direct aXa
No
No
APIXABAN
8-15
50%-85%
(in canine)
25% renal
70% hepatic
b.i.d. oral
direct aXa
No
No
EDOXABAN
7-14
NA
1/3 renal
2/3 hepatic
q.d. oral
direct aXa
No
No
DABIGATRAN
New drugs. New regimens. Why?
• Warfarin is the most commonly used oral anticoagulant, but
problems with both low and high international normalized ratios
(INRs) and issues with adherence have been reported.
• Warfarin is the second most common drug, after insulin,
implicated in adverse events (AE) treated in emergency
departments, representing an estimated 6.2% of annual AE
cases, insulin representing 8%.
Budnitz DS, et al. J Am Med Assoc 2006; 296: 1858–1866.
• In addition, the Food and Drug Administration (FDA) has
recently requested a label update to upgrade the warning of
risk of major or fatal bleeding in patients receiving warfarin,
black-box warning
the
to a
U.S. Food and Drug Administration. 2006 Safety alerts for drugs, biologics, medical devices, and dietary
supplements. October 6, 2006. Available at: http://www.fda.gov/medwatch/safety/2006/safety06.
New drugs. New regimens. Why?
• The anticoagulant effect of warfarin appears
to be affected by interactions with at least 120
foods and drugs
Holbrook AM, et al. Arch Intern Med2005; 165: 10 95–1106.
• A number of new anticoagulant agents are
under investigation or have recently been
approved, some of which reduce the problems
with out-of-range INRs, and may also offer
improved pharmacodynamic properties.
The ideal anticoagulant
...versus currently available agents
No
IDEAL
Fixed
dosing
Rapid
onset/
offset
9
9
9
9
9
9
9
9
9
9
9
LMWH
9
Heparin
9
Fondaparinux
Warfarin
No
No routine
accumulation
No
Predictable coagulation food/drug thromboif renal
response monitoring interactions cytopenia impairment
Oral
9
9
9
9
9
9
9
9
9
Anticoagulants in Development
TTP889
TF/VIIa
TFPI (tifacogin)
NAPc2
IX
X
VIIIa
IXa
Oral
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
YM150
Va
Xa
Oral
Dabigatran
II
IIa
Fibrinogen
APC (drotrecogin alfa)
sTM (ART-123)
Fibrin
Parenteral
Fondaparinux
Idraparinux
Biotinylated idraparinux
Adapted from Bates Br J Haematol 2006
DABIGATRAN ETEXILATE (Pradaxa®)
Dabigatran etexilate is an oral direct thrombin
inhibitor exhibiting:
Predictable anticoagulant effect1-3
Fixed dose:
- No adjustment to body weight etc.
Acts on clot bound and free thrombin
Fast onset and offset
Dabigatran etexilate is the pro-drug of the
active compound dabigatran, which binds
directly to thrombin with a high affinity and
specificity4-5
1. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2004; 2: 1573–1580 2. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2005; 3: 103–111 3. Wallentin L et al. European
Heart Journal 2005; 26(suppl): 482. 4. Stassen JM et al. 28th Congress of the International Society on Thrombosis and Haemostasis; Paris July 6-12, 2001 5. Hauel NH et al. J Med Chem
2002; 45:1757-66
RE-VOLUTION - Trial Program Overview
More than 36,000 patients involved
Dabigatran Clinical Program: REVOLUTION
Phase III Studies in VTE Prophylaxis After THR/TKR
Enoxaparin
40 mg QD* OR
30 mg BID #
Start evening before surgery* or
12-24 hours post-operatively#
Dabigatran etexilate
75 / 150 mg QD
Start 1-4 hours* or
6-12 hours# post-operatively
R
110 / 220 mg QD
Venography
Follow-up
Within 12 hours of last dose
12–14 weeks
*RE-MODEL and RE-NOVATE
#RE-MOBILIZE
Design:
Non-Inferiority in Modified
Intention-To-Treat Population
Study
Therapy
Duration
Enoxaparin
Dose (mg)
RE-MODEL
Knee
6-10 days
40 QD
RE-NOVATE
Hip
28-35 days
40 QD
RE-MOBILIZE
Knee
12-15 days
30 BID
Eriksson et al J Thromb Haemost 2007; Eriksson et al Lancet 2007; Ginsberg et al J Arthroplast. 2008
Dabigatran etexilate versus enoxaparin for prevention of
venous thromboembolism after total hip replacement:
a randomised, double-blind, non-inferiority trial.
Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH,
Hettiarachchi R, Hantel S, Schnee J, Büller HR; RE-NOVATE Study Group
Lancet 2007; 370:949-56.
Primary Efficacy Outcome
Endpoint
Total VTE and all cause
mortality - %
Absolute Difference versus
Enoxaparin - % (95% CI)
P-value for non-inferiority
Eriksson BI et al. Lancet 2007;370:949-56
Enoxaparin
N=897
220 mg
N= 880
150 mg
N=874
6.0
8.6
6.7
-0.7 (-2.9, 1.6)
1.9 (-1.6, 4.4)
-
<0.05
<0.05
Bleeding Outcomes
End point
Enoxaparin
N=1122
220 mg
N= 1116
150 mg
N=1123
Major Bleeding (%)
2.0
1.3
1.6
Major Bleeding Plus Clinically
Relevant Bleeding (%)
6.2
6.0
5.0
12.3
12.2
11.4
Any Bleeding (%)
Eriksson BI et al. Lancet 2007;370:949-56
Oral dabigatran etexilate vs. subcutaneous enoxaparin
for the prevention ofvenous thromboembolism after total
knee replacement: the RE-MODEL randomized trial.
Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kälebo P,
Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Büller HR; RE-MODEL Study Group.
J Thromb Haemost. 2007; 5:2175-7
Total VTE and all cause
mortality - %
Absolute Difference versus
Enoxaparin - % (95% CI)
P-value for non-inferiority
Eriksson BI et al. J Thromb Haemost 2007; 5:2175-7
Enoxaparin
N=512
220 mg
N= 503
150 mg
N=526
36.4
40.5
37.7
-1.3 (-7.3, 4.6)
2.8 (-3.1, 8.7)
-
<0.05
<0.05
Bleeding Outcomes
Dabigatran etexilate (%)
End point
Enoxaparin (%)
N=694
220 mg
N= 679
150 mg
N=703
Major Bleeding*
1.5
1.3
1.3
Major Bleeding Plus
Clinically Relevant Bleeding
7.4
7.1
6.6
Any Bleeding
16.2
16.5
16.6
*No fatal bleeding, one critical organ bleed in each of the dabigatran dose groups
Eriksson BI et al. J Thromb Haemost 2007; 5:2175-7
Conclusions
Results of RE-NOVATE and RE-MODEL:
MODEL
• Both doses of dabigatran proved efficacious and
comparable to enoxaparin for the prevention of major VTE
in orthopedic surgery.
• Showed a low rate of bleeding, comparable with
enoxaparin
• Showed no difference in ACS events or liver enzyme
changes in either of the dabigatran etexilate doses
compared to enoxaparin
• Offered fixed oral dosing without coagulation monitoring
Dabigatran versus Warfarin in the Treatment of
Acute Venous Thromboembolism
The Re-Cover Study
10
Efficacy Endpoints
8
6
Dabigatran
4
2.4%
30/1274
2.1%
27/1265
2
0
VTE
Schulman S, Kearon C, Kakkar AK et al N Engl J Med. 2009; 361: 2342-52
Warfarin
Dabigatran versus Warfarin in the Treatment of
Acute Venous Thromboembolism
The Re-Cover Study
Safety Endpoints
21.9%
(277/1274)
25
16.1%
(205/1274)
20
15
Dabigatran
10
5
Warfarin
1.9%
1.6% (24/1265)
(20/1274)
0
Major
bleedings
Any bleeding
Schulman S, Kearon C, Kakkar AK et al. N Engl J Med. 2009; 361: 2342-52
Rivaroxaban (Xarelto®)
• Oral
• Direct, specific, competitive
FXa inhibitor
• Inhibits free and fibrinbound FXa activity, and
prothrombinase activity
• Effective anticoagulant
• Inhibits thrombin generation
– acts earlier in the
coagulation cascade
• No direct effect on platelet
aggregation
• Effects can potentially be
reversed by recombinant
Factor VIIa, if required
O
O
N
O
N
O
Cl
H
N
S
Rivaroxaban O
Perzborn et al., J Thromb Haemost 2005; Pathophysiol Haemost Thromb 2004; Depasse et al.,
al., J Thromb
Hameost 2005;Kubitza
2005;Kubitza et al.,
al., Clin Pharmacol Ther 2005; Br J Clin Pharmacol 2007; Eur J Clin Pharmacol
2005; Graff et al.,
al., J Clin Pharmacol 2007; Fareed et al.,
al., J Thromb Haemost 2005; Tinel et al.,
al., Blood 2006
Clinical programme overview:
50,000 patients to be enrolled
Phase II
VTE prevention after major
orthopaedic surgery
•
•
•
•
ODIXa-HIP1
ODIXa-HIP2
ODIXa-KNEE
ODIXa-OD-HIP
Phase III
•
•
•
•
RECORD1
RECORD2
RECORD3
RECORD4
VTE prevention in
hospitalized medically ill
patients
VTE treatment
Stroke prevention in atrial
fibrillation
Secondary prevention of
acute coronary syndromes
• ODIXa-DVT
• EINSTEIN-DVT
• EINSTEIN-DVT
• EINSTEIN-PE
• EINSTEIN-EXT
Japanese Phase III study
RECORD: Rivaroxaban Phase III Studies in
VTE Prophylaxis After THR/TKR
R
S
U
R
G
E
R
Y
Mandatory
bilateral
venography
6–8 hours post-surgery
Enoxaparin
Evening before surgery*
Or 12–24 hours post-surgery#
Last dose, day
before venography
Day 1
*RECORD1, 2 and 3
#
RECORD4 12–24 hours post-surgery
‡
followed by oral placebo for 3 weeks
DESIGN:
F
O
L
L
O
W
U
P
Rivaroxaban 10 mg QD
Therapy Duration (weeks) Enoxaparin
Study
Rivaroxaban
Enoxaparin
Dose (mg)
RECORD1
Hip
5
5
40 QD
RECORD2
Hip
5
2‡
40 QD
RECORD3
Knee
2
2
40 QD
RECORD4
Knee
2
2
30 BID
RECORD 1, 3, and 4
Non-Inferiority in per-protocol population
Superiority in modified intention-to-treat population
RECORD 2
Superiority in modified intention-to-treat population
Eriksson et al. New Engl J Med 2008; Kakkar et al. Lancet 2008; Lassen et al. New Engl J Med 2008; Turpie
EFORT 2008
Primary Efficacy Outcome: Total VTE or AllCause Mortality
Enoxaparin
RRR = 78%
Rivaroxaban
ARD = –7.3% (–9.4, –5.2)
RRR = 49%
p<0.0001
ARD = –9.2% (–12.4, –5.9)
p<0.001
RRR = 31%
RRR = 70%
ARD = –3.19% (–5.67, –0.71)
ARD = –2.6% (–3.7, –1.5)
p<0.012
p<0.001
RECORD3
RECORD4
(Knee)
Relative Risk Reduction (RRR) based on raw incidences
Absolute Risk Difference (ARD) (95% CI)
RECORD2
RECORD1
(Hip)
Lassen et al. New Engl J Med 2008; Turpie EFORT 2008
Kakkar et al. Lancet 2008; Eriksson et al. New Engl J Med 2008
Rivaroxaban for the treatment of
venous thromboembolism
EINSTEIN DVT: study design
Randomized, open-label, event-driven, non-inferiority study
Up to 48 hours’ heparins/fondaparinux treatment permitted before study entry
Treatment period: 3, 6 or 12 months
Confirmed
symptomatic
DVT without
symptomatic
PE
Rivaroxaban
Rivaroxaban
N=3,449
R
15 mg bid
20 mg od
Enoxaparin 1.0 mg/kg bid ≥5 days, followed by
VKA INR range 2–3
Day 1
30-day observation
period
88 primary efficacy outcomes needed
Day 21
EINSTEIN DVT trial ID: NCT00440193
58
Study outcomes
Primary efficacy outcome*
• Symptomatic recurrent VTE: composite of recurrent DVT, non-fatal PE
or fatal PE
Principal safety outcome*
• Combination of major and clinically relevant non-major bleeding
Secondary and other outcomes* including:
• Net clinical benefit: primary efficacy outcome + major bleeding
• Total mortality
• Cardiovascular events
Central laboratory
• Monthly ALT and bilirubin testing
*Adjudicated by the central independent and blinded adjudication committee
Primary efficacy outcome analysis
Rivaroxaban
(n=1,731)
First symptomatic recurrent VTE
Recurrent DVT
n (%)
36 (2.1)
n (%)
51 (3.0)
14 (0.8)
28 (1.6)
Recurrent DVT + PE
1 (<0.1)
Non-fatal PE
0
0.68
0 (0)
20 (1.2)
18 (1.0)
4 (0.2)
6 (0.3)
Fatal PE/unexplained death where
PE cannot be ruled out
0.44
Enoxaparin/VKA
(n=1,718)
1.04
1
Hazard ratio
Rivaroxaban superior
p=0.076 for superiority (two-sided)
1.75*
Rivaroxaban non-inferior
p<0.0001 for non-inferiority
(one-sided)
ITT population; *non-inferiority margin required for standalone non-inferiority
Rivaroxaban inferior
Cumulative event rate (%)
Primary efficacy outcome: time to first event
4.0
Enoxaparin/VKA (n=1,718)
3.0
Rivaroxaban (n=1,731)
2.0
1.0
0
0
30
60
90
120 150 180 210 240 270
Time to event (days)
300 330 360
Number of
subjects at risk
Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400
369
363
345
309
266
Enox/VKA
362
337
325
297
264
1,718 1,616 1,581 1,553 1,368 1,358 1,186 380
Principal safety outcome analysis
Rivaroxaban
(n=1,718)
Enox/VKA
(n=1,711)
HR (95% CI)
n (%)
p value
139 (8.1)
138 (8.1)
0.97 (0.76–1.22)
p=0.77
14 (0.8)
20 (1.2)
n
First major or clinically relevant
non-major bleeding
Major bleeding
(%)
Contributing to death
1 (<0.1)
5 (0.3)
In a critical site
3 (0.2)
3 (0.2)
10 (0.6)
12 (0.7)
129 (7.5)
122 (7.1)
Associated with fall in Hb ≥2 g/dl
and/or transfusion of ≥2 units
Clinically relevant non-major bleeding
Safety population
RE-LY – study design
Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
110 mg bid
N=6000
150 mg bid
N=6000
Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin
Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
Stroke or systemic embolism (SSE)
RR 0.91 (95% CI: 0.74–1.11)
p<0.001 (NI)
1,8
1,5
RR 0.66 (95% CI: 0.53–0.82)
p<0.001 (sup)
1,69
1,53
RRR
34%
% per year
1,2
1,11
0,9
0,6
0,3
0
D110 mg BID
182 / 6,015
D150 mg BID
134 / 6,076
Warfarin
199 / 6,022
Major bleeding rates
RR 0.80 (95% CI: 0.69–0.93)
3,50
p=0.003 (sup)
RRR
20%
3,00
% per year
2,50
RR 0.93 (95% CI: 0.81–1.07)
p=0.31 (NI)
3,36
3,11
2,71
2,00
1,50
1,00
0,50
0,00
D110 mg BID
D150 mg BID
Warfarin
322 / 6,015
375 / 6,076
397 / 6,022
Hemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)
p<0.001 (sup)
Number of events
50
RR 0.26 (95% CI: 0.14–0.49)
p<0.001 (sup)
45
40
RRR
74%
RRR
69%
0.38%
30
20
10
0
14
0.12%
D110 mg BID
6,015
12
0.10%
D150 mg BID
6,076
Warfarin
6,022
Conclusions
• Dabigatran etexilate has shown to concurrently reduce both
thrombotic and hemorrhagic events
• Both doses of dabigatran provide different and
complementary advantages over warfarin
• 150 mg BID has superior efficacy with similar bleeding
• 110 mg BID has significantly less bleedings with
similar efficacy
• Similar net clinical benefit was seen between the two
dabigatran doses
Stroke Prevention Using the Oral Direct Factor Xa
inhibitor Rivaroxaban Compared with Warfarin in
Patients with Nonvalvular Atrial Fibrillation
(ROCKET AF)
AHA Chicago, November 15, 2010
Rocket Study – Per Protocol Population
p<0.015 (sup)
2,4
2,1
2,15
% per year
1,8
1,5
1,70
1,2
0,9
0,6
0,3
0
Riva 20 mg
Warfarin
Rocket Study – Intention To Treat Population
p<0.001 (non inf)
2,4
2,1
2,42
2,12
% per year
1,8
1,5
1,2
0,9
0,6
0,3
0
Riva 20 mg
Warfarin
Rocket Study
Primary efficacy endpoint
Per Protocol Population
• Rivaroxaban was superior to warfarin, delivering
a 21% relative risk reduction in stroke and nonCNS systemic embolism in the pre-specified on
treatment population
Intention To Treat Population
• This result indicates that the treatment benefits
compared to warfarin were sustained as long as the
patients received rivaroxaban.
Rocket Study –
Major and non-Major Bleeding Rates
p=0.442
16,00
14,00
14,91
14,52
Riva 20 mg
Warfarin
% per year
12,00
10,00
8,00
6,00
4,00
2,00
0,00
Rocket Study
Intracranial Hemorrhages
1,00
p=0.019
% per year
0,74
0,50
0,49
0,00
Riva 20 mg
Warfarin
Rocket Study
• In addition, significantly fewer cases of
hemorrhagic stroke, one of the most severe types
of stroke, were observed in patients on
rivaroxaban (0.26% vs. 0.44% p=0.024).
• Compared to warfarin, rivaroxaban also showed
numerically fewer cases of myocardial infarction
(0.91% vs. 1.12%, p=0.121), and an observed
reduction in rates of all-cause mortality (1.87% vs.
2.21%, p=0.073).
STRATIFICAZIONE DEL RISCHIO E
PROFILASSI CONSIGLIABILE
Fondazione IRCCS Policlinico di Pavia
Livelli di
Rischio
Basso Rischio
Rischio
Intermedio
o Moderato
Senza
Profilassi
Chirurgia minore in pazienti mobili
Pazienti internistici allettati
Maggior parte dei pazienti sottoposti a
procedure di chirurgia generale,
urologica, ginecologica.
<10%
15%-40%
Profilassi Raccomandata
Nessuna profilassi specifica ma
deambulazione precoce e
“aggressiva”
Eparina a Basso Peso Molecolare
(EBPM) alle dosi raccomandate (vedi
tabella 4)
Eparina Calcica b.i.d. oppure t.i.d.
Fondaparinux
Se rischio moderato associato ad elevato
rischio emorragico
Profilassi meccanica**
Protesi elettiva d’anca o di ginocchio,
frattura d’anca
tabella 4)
Fondaparinux
Dabigatran (solo per chirurgia
protesica d’anca o di ginocchio)
Alto Rischio
40%-80%
Trauma maggiore, trauma spinale
Se alto rischio associato ad elevato
rischio emorragico
Rivaroxaban (solo per chirurgia
protesica d’anca o di ginocchio)
tabella 4)
Profilassi meccanica**
Schema di dosaggio per la profilassi antitrombotica
utilizzando i farmaci disponibili nella Fondazione IRCCS Policlinico San Matteo
SCORE
RISCHIO
≤1
Basso
1.5 – 2.5
≥3
Moderato
Alto
PROVVEDIMENTO
Calze elastiche a compressione graduata
Mobilizzazione precoce
Enoxaparina – 0.2 ml, 2000 UI aXa/die
Nadroparina – 0.3 ml, 2850 UI aXa/die, a dose
variabile secondo il peso (vedi scheda tecnica del
farmaco)
Eparina Calcica – 0.2 ml, 5.000 U.I. x 3 vv. al dì
Iniziare 12 ore prima dell’intervento o entro le 12
ore successive
Fondaparinux 2,5 mg/die, iniziando 6-8 ore dopo
l’intervento
Enoxaparina – 0.4 ml, 4000 UI aXa/die
Nadroparina 0.4 ml– 3750 UI aXa/die, modificando
la dose con giornata post-operatoria (vedi scheda
tecnica)
Iniziare 12 ore prima dell’intervento o entro le 12
ore successive
Fondaparinux 2,5 mg/die, iniziando 6-8 ore dopo
l’intervento
Solo per chirurgia ortopedica
protesica d’anca o di ginocchio
Alto
Enoxaparina – 0.4 ml, 4000 UI aXa/die oppure
Nadroparina 0.4 ml– 3750 UI aXa/die, modificando
la dose con giornata post-operatoria (vedi scheda
tecnica). Iniziare 12 ore prima dell’intervento o
entro le 12 ore successive
Dabigatran 150 o 220 mg/die, iniziando 4 ore dopo
l’intervento (vedi raccomand. specifiche per prima
dose)
Rivaroxaban 10,0 mg, iniziando 6-1\0 ore dopo
l’intervento (vedi raccomandazioni specifiche)
2008 ACCP Recommendation
for Medical Conditions
• For acutely ill medical patients admitted to hospital with
congestive heart failure or severe respiratory disease, or who
are confined to bed and have one or more additional risk
factors, including active cancer, previous VTE, sepsis, acute
neurologic disease, or inflammatory bowel disease, we
recommend thromboprophylaxis with LMWH (Grade 1A),
LDUH (Grade 1A), or fondaparinux (Grade 1A).
• For medical patients with risk factors for VTE, and for
whom there is a contraindication to anticoagulant
thromboprophylaxis, we recommend the optimal use of
mechanical thromboprophylaxis
with GCS or IPC (Grade 1A).
PE Kills 3 Times More Medical
Patients Than Surgical Patients
25%
Medical patients
Surgical patients
75%
Sandler DA, et al. J R Soc Med. 1989;82:203-5.
Summary of venous thromboembolic
events during the treatment period
(%)
P = 0.0002
16
Placebo
14
RRR = -63%
Enoxaparin 20 mg
12
10
Enoxaparin 40 mg
8
P = 0.037
6
RRR = -65%
4
NS
2
0
All VTE
NS = not significant
Proximal DVT
PE
ARTEMIS
ARixtra® for
ThromboEmbolism prevention in a
Medical Indications Study
AT Cohen, B Davidson, A Gallus, MR Lassen,
W Tomkowski and AGG Turpie
On behalf of the ARTEMIS Investigators
VTE Up to Day 15
Odds Reduction =
% of VTE
12
10
8
6
4
49.5%
(95%CI: 72.1; 8.6)
10.5%
34/323
5.6%p = 0.029
18/321
2
0
Fondaparinux
Placebo
EXCLAIM: Study design

Multicenter, Prospective, Randomized, Double-blind, Placebo-controlled study to
demonstrate superiority of enoxaparin 40 mg sc qd for 28 days + 4 days compared
with placebo both following 10 + 4 days of initial treatment with enoxaparin 40
mg sc qd
Enoxaparin 40 mg sc od
Enoxaparin
40 mg sc od R
Open-label
Da0
y
10 + 4
qd = once a day, SC = subcutaneous
Placebo
Double-blind
Follow-up
38 ± 4 180 ± 10
Mandatory
ultrasonography
Hull RD Ann Intern Med 2010
EXCLAIM Efficacy
all VTE until Day 90
Placebo
Enoxaparin
p = 0.0011
p = 0.0115
5.2
4.9
RRR
-
RRR
Incidence (%)
44%
2.8
Day 38
42%
3.0
Day 90
Hull RD Ann Intern Med 2010
Rivaroxaban compared with enoxaparin
for the prevention of venous
thromboembolism in acutely ill medical
patients
MAGELLAN Investigators
MAGELLAN: clinical trial design
Day 10
(6–14)
8,101 patients
randomized
Day 35
(31–39)
Day 90
(83–97)
Oral rivaroxaban 10 mg od 35±4 days
Patients
≥40 years
hospitalized for
acute medical
illness with
decreased level
of mobility
s.c. placebo
10±4 days
R
Follow-up
period
to Day 90
Oral placebo
35±4 days
s.c. enoxaparin
40 mg od 10±4 days
Ultrasonography
on day 10±4
Primary efficacy outcome
Day 10 (non-inferiority)
*Includes events from
from Day 1 to Day 35
Cohen et al,
,
2011
al
Ultrasonography
on day 35±4
Day 35* (superiority)
Primary efficacy outcome: Day 10*
Rivaroxaban
(n=2,939)
n (%)
78 (2.7)
71 (2.4)
7 (0.2)
6 (0.2)
3 (0.1)
Asymptomatic proximal DVT
Symptomatic lower extremity DVT
Symptomatic non-fatal PE
VTE-related death‡
0.71
0.97
Enoxaparin
(n=2,993)
n (%)
82 (2.7)
71 (2.4)
6 (0.2)
2 (<0.1)
6 (0.2)
1.31
1.50 p=0.0025 for non-inferiority
1.00
Relative risk ratio
(one-sided)
0
Superior
Noninferior
Inferior
*PP population, events up to Day 10+5 days; ‡includes cases where PE cannot be ruled out
Primary efficacy outcome: Day 35*
Rivaroxaban
(n=2,967)
n (%)
131 (4.4)
103 (3.5)
13 (0.4)
10 (0.3)
19 (0.6)
Asymptomatic proximal DVT
Symptomatic lower extremity DVT
Symptomatic non-fatal PE
VTE-related death‡
0.62
0
0.77
0.96
1.00
Relative risk ratio
Superior
Noninferior
Enoxaparin/
placebo
(n=3,057)
n (%)
175 (5.7)
133 (4.4)
15 (0.5)
14 (0.5)
30 (1.0)
ARD: 1.3%
RRR: 22.9%
p=0.0211 for superiority
(two-sided)
Inferior
*mITT population, events up to Day 35+6 days; ‡4 confirmed fatal PEs includes cases where PE
cannot be ruled out
Safety outcomes
Rivaroxaban
(n=3,997)
Enoxaparin/
placebo
(n=4,001)
n (%)
n (%)
RR
p value
Day 1 to 10 (principal safety outcome)
Clinically relevant bleeding*
Major bleeding
111 (2.8)
49 (1.2)
2.3
<0.0001
24 (0.6)
11 (0.3)
2.2
0.0318
164 (4.1)
67 (1.7)
2.5
<0.0001
43 (1.1)
15 (0.4)
2.9
0.0004
56 (1.4)
19 (0.5)
3.0
<0.0001
19 (0.5)
4 (0.1)
4.8
0.0045
Day 1 to 35 (principal safety outcome)
Major bleeding
Day 11 to 35
Major bleeding
*Major plus non-major clinically relevant bleeding
Safety population; treatment-emergent bleeding
Components of major bleeding
Rivaroxaban
(n=3,997)
Enoxaparin/
placebo
(n=4,001)
n (%)
n (%)
24 (0.6)
11 (0.3)
Fall in hemoglobin ≥2g/dl
17 (0.4)
7 (0.2)
Transfusions ≥2 units of blood
15 (0.4)
5 (0.1)
Critical site†
5 (0.1)
3 (0.1)
Fatal
5 (0.1)
1 (<0.1)
19 (0.5)
4 (0.1)
14 (0.4)
3 (<0.1)
Transfusions ≥2 units of blood
9 (0.2)
3 (<0.1)
Critical site†
4 (0.1)
1 (<0.1)
Fatal
2 (<0.1)
0
Day 1 to 10
Major bleeding*
Day 11 to 35
Major bleeding*
Fall in hemoglobin ≥2g/dl
*Patients could have a bleeding event in more than one subcategory; †defined as intracranial,
intraspinal, intraocular, retroperitoneal, intra-articular, pericardial or intramuscular with
compartment syndrome
“In the final analysis, the
therapeutic efficacy of any drug
can only be demonstrated by
clinical trials in man”
Annotation,
British Journal of Haematology 1984